Benzenesulfonyl-ureas and process for their preparation

ABSTRACT

R1 represents hydrogen, lower molecular alkyl, acyl, phenyl, R2 is hydrogen, lower molecular alkyl, R3 is alkyl having 3 to 6 carbon atoms, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, cycloalkenyl, alkylcycloalkenyl having each 5 to 9 carbon atoms, cyclohexenylmethyl, chlorocyclohexyl, bicycloheptenylmethyl, bicycloheptylmethyl, bicycloheptenyl, bicycloheptyl, nortricyclyl, adamantyl, benzyl, phenylethyl, which as substance or in the form of their salts have pypoglycemic properties and which are distinguished by a strong and continuous lowering of the blood sugar level; processes for preparing them as well as pharmaceutical preparations containing the sulfonyl-ureas as an active substance.   IN WHICH X represents hydrogen, chlorine, bromine, methoxy or methyl, Y represents -CH(CH3)-CH2-, -CH2-CH(CH3)-or preferably -CH2-CH2-, Z represents hydrogen or together with Y and the phenylene radical the radical   Sulfonyl-ureas of the formula

United States Patent [1 1 Weyer et al.

[451 Sept. 10, 1974 BENZENESULFONYL-UREAS AND PROCESS FOR THEIR PREPARATION [75] Inventors: Rudi Weyer, Frankfurt/Main;

Volker Hitzel, Lorsbach/Taunus; Walter Aumiiller, Kelkheim/Taunus;

Ruth Heerdt, Mannheim, all of Germany [73] Assignee: Farbwerke Hoechst Aktiengesellschaft vormals Meister Lucius & Bruning, Frankfurt/Main, Germany [22] Filed: June 20, 1973 [2l] Appl. No.: 371,663

[30] Foreign Application Priority Data June 22, 1972 Germany; 2230543 [52] U.S. Cl 260/553 DA, 260/556 B, 424/322 [51] Int. Cl. C07c 127/12 [58] Field of Search 260/553 DA [56] References Cited UNITED STATES PATENTS 3,426,067 2/l969 Weber et al. 260/553 DA Primary Examiner-Leon Zitver Arsistant Examiner-Gerald A. Schwartz Attorney, Agent, or FirmCurtis, Morris & Safford [57] ABSTRACT Sulfonyl-ureas of the formula in which X represents hydrogen, chlorine, bromine, methoxy or methyl, Y represents -CH(CH )-Cl-l CH Cl-l(CH )or preferably Cl-l -CH Z represents hydrogen or together with Y and the phenylene radical the radical 6 Claims, N0 Drawings which as substance or in form of the salts thereof have hypoglycemic properties and are distinguished by a strong and continuous lowering of the blood sugar level.

mine, methoxy or methyl, Y is CH(CH )CH CH CH(CH or preferably CH CH Z represents hydrogen or together with Y and the phenylene radical the radical BENZENESULFONYL-UR EAS AND PROCESS FOR THEIR PREPARATION The present invention relates to sulfonyl-ureas of the formula 5 In the formula X represents hydrogen, chlorine, bro- The term lower molecular alkyl used in the above meanings defines a straight-chained or branched alkyl having 1 to 4 carbon atoms. Acyl is preferably an alkanoyl having 2 to 7 carbon atoms.

The invention further relates to processes for preparing these sulfonyl-ureas. They comprise, if R is not identical to hydrogen,

a. reacting sulfonyl-carbamic acid esters, sulfonyl-thiolcarbamic acid esters, sulfonyl-ureas, sulfonyl-semicarbazides or -semicarbazones substituted by the group with an amine R NH or the salts thereof or reacting sulfon-amides of the formula or the salts thereof with R -substituted isocyanates, carbamic acid esters, thiolcarbamic acid esters, carbamic acid halides or ureas,

b. saponifying or hydrolizing correspondingly substituted sulfonyl-isourea ethers, isothioura ethers, -parabanic acids or -haloformic acid amines,

c. replacing in corresponding sulfonylthio-ureas substituted by the group the thiosulfur atom by oxygen,

(1. adding water onto correspondingly substituted carbodiimides,

e. introducing into sulfonyl-ureas of the formula the radical by acylation, if desired, in one or more steps or f. reacting correspondingly substituted sulfonylhalides with R -substituted ureas or the alkali salts thereof or reacting correspondingly substituted sulfinic acid halides or, in the presence of an acid condensation agent, correspondingly substituted sulfinic acids or the alkali salts thereof with hydroxy ureas of the formula or, if R and R are identical to hydrogen g. reducing sulfonyl-ureas of the formula at the nitro group and treating the reaction products, if desired, with alkaline agents for the formation of salts.

If R, and R represent hydrogen the sulfonyl-ureas are obtained by reduction of the nitro compounds, whereby the nitro compounds themselves can be prepared according to the above processes. The benzenesulfonyl-carbamic acid esters or benzenesulfonyl-thiolcarbamic acid esters may contain in the alcohol component an alkyl radical or an aryl radical or a heterocyclic radical. Since this radical is split off during the reaction the chemical constitution thereof has no influence on the nature of the final product and may, thus, be varied within wide limits. The same applies to N-R -substituted carbamic acid esters or to the corresponding thiolcarbamic acid esters.

As carbamic acid halides the chlorides are preferably used.

The sulfonyl-urea used as starting materials of the process can be unsubstituted, monoor especially disubstituted at the side of the urea molecule opposite to the sulfonyl group. Since these substituents are split off in the reaction with amines, their nature may be varied within wide limits. In addition to alkyl, acyl, aryl or heterocylically substituted benzenesulfonyl-ureas there may also be used sulfonyl-carbamoylimidazoles and similar compounds or bisbenzenesulfonyl-ureas which may carry on one of the nitrogen atoms one further substituent, for example methyl. Those bis- (benzenesulfonyl)-ureas may be treated for example with R substituted amines and the salts obtained heated to elevated temperatures, especially to a temperature about 100C.

Furthermore it is possible to'start from R -substituted ureas or from those R -substituted ureas which are monoor especially di-substituted at the free nitrogen atom, in order to react these ureas with sulfonamides carrying the substituent As such starting materials may be used for example N-cyclohexyl-urea, the corresponding N-acetyl, N- nitro, N-cyclohexyl, N,Ndiphenyl-ureas (whereby both phenyl radicals may also be substituted or linked to each other either directly or by means of a bridge member such as CH NH, -O or S), N-methyl-N-phenyl-, N',N-dicyclohexyl ureas as well as cyclohexyl-carbamoylimidazoles, pyrazoles or triazoles as well as those of the compounds mentioned which carry instead of the cyclohexyl another substituent having one of the definitions given for R ide, sodium peroxide, nitrous acid permanganates.

The thioureas may also be desulfurized by treatment with phosgene or with phosphorus pentachloride. Chloroformic acid amidines or carbodiimides obtained as an intermediate stage may be converted into the sulfonyl ureas by suitable measures, for example, by saponification or addition of water.

With regard to some oxydating agents, for example hydrogen peroxide, the isothiourea ethers have the same behaviour as the corresponding thioureas. Therefore, those ethers can be used like the ureas as starting substances for oxydative desulfurization.

The methods described concern sulfonyl-ureas wherein R and R are not identical to hydrogen. If R, and R represent hydrogen the compounds are obtained in usual manner by the reduction of nitro compounds.

As regards the reaction conditions the variations of carrying out the process of the invention may, in general, be modified within wide limits and adapted to each individual case. For example, the reactions may be carried out with the use of solvents or without solvents, at room temperature or at an elevated temperature.

Depending on the nature of the starting substances, one or other of the variations of the process hereinbefore described may, in some cases, provide a desired, individual sulfonyl-urea only in a small yield or may be inappropriate for its synthesis. In such comparatively rare cases the expert will have no difficulty in synthesizing the desired produce according to one of the other methods of the process described.

The hypoglycemic action of the benzenesulfonylureas described can be ascertained by administering them as free compounds or in the form of the sodium salts, to normally fed rabbits, in doses of 10 mg/kg of body weight and determining the blood sugar level according to the known method of Hagedorn-Jensen or by means of an autoanalyser for a prolonged period of time.

TABLE Lowering of the blood sugar in rabbits in after administration of IO/kg of N-[4-(B- 2-dimethylaminobenzamido -ethyl)- benzenesulfonyl]-N'- (4-methylcyclohexyl)-urea (compound 1) and N-[4- B- 2-anilino-5chloro-benzamido -ethyl benzenesulfonyl]-N-cyclohexylurea (compound 2) orally after hours.

Hours 1 3 6 24 33 48 72 Compound 1 27 35 35 31 23 0 0 Compound 2 20 21 20 23 1 6 0 The benzenesulfonyl-ureas described are preferably used for the preparation of pharmaceutical preparations suitable for oral administration and for the lowering of the blood sugar level in the treatment of diabetes mellitus and may be used as such or in the form of their salts or in the presence'of substances which cause such salt formation. For the formation of salts, there may be used, pharmaceutically acceptable bases for example, bases such as alkali metal or alkaline earth metal hydroxides or alkali metal or alkaline earth metal carbonates or bicarbonates.

The pharmaceutical preparations are advantageously in the form of tablets which contain in addition to the products of the invention the pharmaceutically suitable carriers such as talc, starch, lactose, tragacanth or magnesium stearate.

A pharmaceutical preparation containing the sulfonyl-ureas described as the active substance, for example, a tablet or a powder with or without carriers, is advantageously brought into a suitable unit dosage form. The dose chosen should comply with the activity of the sulfonyl-urea used and with the desired effect. Advantageously, the dosage per unit amounts to about 0.5 to 100 mg, preferably 2 to mg, but higher or lower dosage units may also be used, which, if desired, are divided or multiplied prior to their administration.

The sulfonyl-ureas of the invention may be used ei- EXAMPLE 1 N-[4-(B-Z-amino-benzamidoethyl)-benzenesulfonyl]- N-cyclohexyl-urea 17.4 Grams of 4-(,B-Z-nitrobenzamidoethyl)- benzenesulfonamide (melting point 202 to 204C prepared from 2-nitrobenzoyl chloride and 4-(B- aminoethyl)-benzenesulfonamide) were mixed in 200 ml of acetone with the solution of 2 g of NaOH in water. 6.5 Grams of cyclohexylisocyanate were added to this mixture while stirring, being cooled occasionally; stirring was continued for 2 hours at room temperature; after addition of water and hydrochloric acid the mixture was suction-filtered. The reaction product was recrystallized from diluted ethanol and melted at 208 to 210C.

Grams of N-[4-(B-Z-nitrobenzamidoethyl)- benzenesulfonyl]-Ncyclohexyl-urea were hydrogenated in 500 ml of methanol in the presence of Raney- Nickel at room temperature and under normal pressure. After finishing the absorption of hydrogen the catalyst was suction-filtered, the solvent was evaporated under reduced pressure and the residue was recrystallized from diluted ethanol. The N-[4-(B-2- amino-benzamidoethyl)-benzenesulfonyl]-N- cyclohexyl-urea obtained melted at 160 to 162C In analogous manner was obtained from the N-[4-(B- 2-nitrobenzamidoethyl)-benzenesulfonyl]-N-(4-ethylcyc1ohexyl)-urea (melting point 189191C) the N-[4- (B-Z-aminobenzamidoethyl)-benzenesulfonyl]-N-(4- ethyl-cyclohexyl)-urea having a melting point of 133l35C (from diluted ethanol).

In analogous manner was obtained from the N-[4-(B- 4-methyl-2-nitrobenzamido -ethy1)- benzenesulfonyl]-N' cyc1ohexyl-urea having a melting point of 208210C,

the N-[4-( B- 4-methyl-2-aminobenzamido -ethyl benzenesulfonyl]-N-cyclohexyl-urea having a melting point of 184-186C (from ethanol), by means of the N- 4-( B- 4-methyl-2-nitrobenzamido -ethyl benzenesulfonyl[-N-(4-methylcyclohexyl)-urea having a melting point of C to 187C the N-[4-(B- 4- methyI-Z-aminobenzamido -ethyl )-benzc nesulfonyl N'-(4-methylcyclohexyl)-urea having a melting point of 172174C (from ethanol).

In analogous manner was obtained by means of the N-[4-(B- 3-methyl-2-nitro-benzamido -ethyl)- benzene-sulfonyl]-N-cyclohexyl-urea having a melting point of 200-202C the N-[4-(B- 3-methyl-2-aminobenzamido -ethyl)-benzene-sulfonyl]-N'-cyclohexylurea having a melting point of l96l 98C by means of the N-[4-(,B-5-chloro-2-nitro-benzamidoethyl)- benzenesulfonyl]-N-cyclohexyl-urea having a melting point of 196C the N-[4-(B-5-chloro-2-aminobenzamidoethyl)-benzene-sulfonyl]-N-cyclohexylurea having a melting point of 171-173C (from ethanol) by means of the N-[4-(B-5-chloro-2-nitro-benzamidoethyl)-benzenesulfonyl]-N-4-methylcyclohexyl-urea having a melting point of 191-192C the N-[4-(B-5-chloro-2- aminobenzamidoethyl )-benzene-sulfonyl -N -4- methylcyclohexyl-urea having a melting point of l59161C (from ethanol) by means of the N-[4-(B-5-chloro-2-nitro-benzamidoethyl)-benzenesulfonyl]N-4-ethylcyclohexyl-urea having a melting point of 201-203C the N-[4-(B-5-chloro-2-aminobenzamidoethyl )-benzene-sulfonyl ]-N-4-ethylcyclohexyl-urea having a melting point of 152-154C (from ethanol) and by means of the N-[4-(B- 3-methyl-2-nitro-benzamido -ethyl)-benzene-sulfonyl]-N-4-methyl-cyclohexyl-urea having a melting point of 209-21 1C the N-[4-(B- 3-methyl-2- amino-benzamido -ethyl)-benzenesulfonyl]-N-4- methyl-cyclohexyl-urea having a melting point of 173175C.

EXAMPLE 2 N-[4-(,8-2-acetamidobenzamidoethyl)- benzenesulfonyl]-N-cyclohexyl-urea 14.1 Grams of 4-(B-4-acetamidobenzamidoethyl)- benzenesulfonamide (melting point 2l3215C, prepared by reduction of 4-(B-Z-nitrobenzamidoethyl)- benzenesulfonamide with hydrogen in the presence of Raney Nickel and acetylation of the amino compound) were mixed in 200 ml of acetone with 1.5 g of NaOH in water and reacted, while cooling occasionally, with 5.1 g of cyclohexylisocyanate. Stirring was continued for 2 hours at room temperature, the mixture was mixed with water, acidified, suction-filtered, the ammonia was precipitated and recrystallized from diluted ethanol. The N-[4-(B-2-acetamidobenzamidoethyl)- benzenesulfonyl]-N-cyclohexyl-urea obtained melted at 176l78C.

In analogous manner was obtained the N-[4-(B-Z-acetamidobenzamidoethyl)- benzenesulfonyl]-N-(4-methyl-cyclohexyl)-urea having a melting point of l92194C (from diluted ethanol).

In analogous manner was obtained by means of the 4-(B-2-isobutyramidobenzamidoethyl)- benzenesulfonamide (melting point 194196C, prepared from 4-(B-2-aminobenzamidoethyl)- benzenesulfonamide and isobutyric acid chloride) the N-[4-([3-2-isobutyramidobenzamidoethyl)- benzenesulfonyl]-N'-cyclohexyl-urea having a melting point of l28-l30C (from diluted ethanol), the N-[4- (B-2-isobutyramidobenzamidoethyl)- benzenesulfonyl]-N-(4-methylcyclohexyl)-urea having a melting point of l84l 86C (from diluted ethanol).

In analogous manner was obtained from the 4-(B-2-capronamidobenzamidoethyl)- benzcnesulfonamide (melting point 18l-l83C, prepared from 4-(B-2-aminobenzamidoethyl)- benzenesulfonamide and caproic acid chloride) the N- 4-( B-2-capronamidobenzamidoethyl benzenesulfonyl]-N-cyclohexyl-urea having a melting point of l53l55C (from diluted ethanol),

the N-[ 4-( B-2-capronamidobenzamidoethyl benzenesulfonyl]-N-(4-methylcyclohexyl)-urea having a melting point of l78180C (from diluted methanol).

In analogous manner was obtained from the 4-(B-2- N-methylacetamido -benzamidoethyl)- benzenesulfonamide (melting point 2l8-220C, prepared from 4-(B-2-methylaminobenzamidoethyl)- benzenesulfonamide and acetic acid anhydride) the N- [4-(B-2- N-methylacetamido -benzamidoethyl)- benzenesulfonyl]-N-(4-methylcyclohexyl)-urea having a melting point of l60-l 63C (from diluted ethanol).

In analogous manner was obtained from the 4-(B-2-anilinobenzamidoethyl)-benzenesulfonamide (melting point l93-195C, prepared from the mixed anhydride of the diphenylamino-2-carboxylic acid and 4-(B-aminoethyl)-benzenesulfonamide) the N-[4-(B-Z-anilinobenzamidoethyl)- benzenesulfonyl]-N'-cyclohexyl-urea having a melting point of l75-l77C (from ethanol/DMF),

the N-[4-(B-2-anilinobenzamidoethyl)- benzenesulfonyl]-N-(4-methylcyclohexyl)-urea having a melting point of l96198C (from ethanol/DMF).

In analogous manner was obtained from the 4-(B- 2-aniline-5-chloro-benzamido -ethyl)- benzenesulfonamide (melting point l9ll93C, prepared from the mixed anhydride of the 4-chlorodipheny]amino-2-carboxylic acid and 4-(B- aminoethyl)-benzenesulfonamide) I the N- [4-(B- 2-anilino-5-chloro-benzamido ethyl)-benzenesulfonyl]-N'-cyclohexylurea having a melting point of l85l87C (from methanol/water), from the 4-(B- 2-anilino-5-methoxy-benzamido -ethyl)- benzenesulfonamide (melting point l38140C, prepared from the mixed anhydride of the 4-methoxydiphenylamino-Z-carboxylic acid and 4-(B- aminoethyl)-benzenesulfonamide) the N-[4-(B- 2-anilino-5-methoxy-benzamido ethyl )-benze nesulfonyl -N '-cyclohexyl-urea having a melting point of l60l 61C (from ethanol/water) and the N-[4-(B- 2-anilino-5-methoxy-benzamido -ethyl)- benzenesulfonyl]-N'-(4-methylcyclohexyl)-urea having a melting point of l38140C (from methanol/dioxane/water).

EXAMPLE 3 N -[4-( B- 2-acetamido-5-chloro-benzamido -ethyl benzenesulfonyl]-N-cyclohexyl-urea 21.3 Grams of 2-acetamido-5-chloro-benzoic acid were mixed in 400 ml of tetrahydrofurane with 30.0 g

of triethyl amine. While cooling with ice and stirring 11.4 g of chloroformic acid methyl ester were added dropwise to this mixture and stirring was continued for 30 minutes. 24.8 Grams of 4-(B-aminoethy])-benzenesulfonamide hydrochloride were added portion wise to this suspension and stirring was continued for 4 hours at room temperature. After removing the solvent under reduced pressure the residue was taken up in diluted sodium hydroxide solution, filtered with the addition of coal and acidified with diluted hydrochloric acid. The deposit formed was reprecipitated again. The 4-(B- 2- acetamido-S-chloro-benzamido -ethyl)-benzenesulfonamide thus obtained was recrystallized from ethanol-dioxane-water and melted at 242244C.

12.5 Grams of 4-(B- 2-acetamido-5-chlorobenzamido -ethyl)-benzenesulfonamide were refluxed in 100 ml of dioxane and 100 ml of acetone together with 8.85 g of potassium carbonate (ground) for 2 hours, while stirring. After adding dropwise 3.9 g of cyclohexylisocyanate stirring was continued for another seven hours under reflux, the deposit formed was suction-filtered, dissolved in water, filtered with coal and acidified with diluted hydrochloric acid. Having suction-filtered the N-[4-(,8- 2-acetamido-5-chlorobenzamido -ethyl)-benzenesulfonyl]-N-cyclohexylurea was recrystallized from methanol/water and melted at l96197C.

In analogous manner were obtained the N-[4-(B- 2-acetamido-5-chloro-benzamido ethyl )-benzenesulfonyl -N 4-methyl-cyclohexyl urea having a melting point of l84l86C (from methanol-dioxane-water) N-[4-(B- 2-acetamido-S-chloro-benzamido ethyl)-benzenesulfonyl]-N-butyl-urea having a melting point of 204206C (from nitromethane).

EXAMPLE 4 N-[4-B- 2-dimethylaminobenzamido -ethyl)- benzenesulfonyl]-N'-cyclohexyl-urea 166 Grams of 2-dimethylamino-benzoic acid were dissolved together with 30 g of triethylamine in 400 ml of tetrahydrofurane. While cooling with ice, 11.8 g of chloroformic acid methyl ester were added dropwise, stirring was continued for 30 minutes while cooling and subsequently 24.8 gof 4-(B-amino-ethyl)- benzenesulfonamide hydrochloride were introduced in small amounts. After a reaction time of 4 hours the solvent was evaporated under reduced pressure, the residue was taken up in diluted sodium hydroxide solution, filtered with coal and acidified with acetic acid. The deposit obtained of the 4-(B- 2-dimethylaminobenzamido -ethyl)-benzenesulfonamide became gradually crystalline and melted at l53-l 54C after recrystallization from diluted methanol.

7.3 Grams of 4-(B- 2-dimethylamino-benzamido ethyl)-benzenesulfonamide were dissolved in 10 ml of 2N-sodium hydroxide solution and ml of acetone and while cooling with ice, 2.75 g of cyclohexylisocyanate were added dropwise. Stirring was continued for 3 hours at room temperature, the deposit precipitated was dissolved with water, filtered and acidified with 2N-acetic acid. The N-[4-(B- 2- dimethylaminobenzamido -ethyl)-benzenesulfonyl]- N'-cyclohexyl-urea precipitated was suction-filtered, recrystallized from methanol-dioxane-water and melted at 2l22l3C.

In analogous manner were obtained the N-[4-(B- 2- dimethylaminobenzamido -ethyl)-benzenesulfonyl]- N'-(4-methylcyclohexyl)-urea having a melting point of 192193C (from methanol-dioxane-water) N-[4-(B- Z-dimethylaminobenzamido -ethyl benzenesulfonyl]-N'-butyl-urea having a melting point of 165-166C (from methanol-dioxane-water) N-[4-(B- 2-dimethylaminobenzamido -ethyl)- benzenesulfonyl]-N'-A3-cyclohexenyl-urea having a melting point of 207208C (from methanol/dioxane) N-[4-(B- 2-dimethylaminobenzamido -ethyl)- benzenesulfonyl]-N'-cycloheptyl-urea having a melting point of l84-l85C (from methanol) N-[4-(B- 2-dimethylaminobenzamido -ethyl)- benzenesulfonyl]-N'-(4ethylcyclohexyl)-urea having a melting point of 208210C (from methanol/water) N-[4-(B- 2-dimethylaminobenzamido -ethyl)- benzenesulfonyl]-N'-(2.5-endoethylene-cyclohexyl)- urea having a melting point of 199201C (from methanol).

N-[4-(B- 2-dimethylaminobenzamido -ethyl)- benzenesulfonyl]-N'-(4,4-dimethylcyclohexyl)-urea having a melting point of 195197C (from methanol/- water) N-[4-(B- dimethylaminobenzamido -ethyl)- benzenesulfonyl]-N'-isobutyl-urea having a melting point of l72-l73C (from methanol/water) N-[4-(B- Z-dimethylaminobenzamido -ethyl)- benzenesulfonyl]-N-cyclopentyl-urea having a melting point of 195-l96C (from methanol) N-[4-(B- 2-dimethylaminobenzamido -ethyl)- benzenesulfonyl]-N-cyclopentylmethyl-urea having a melting point of 173l74C (from methanol) N-[4-(B- Z-dimethylaminobenzamido -ethyl)- benzenesulfonyl]-N-B-phenylethyl-urea having a melting point of l82-l83C (from methanol) N-[4-(B- 2-dimethylaminobenzamido -ethyl)- benzenesulfonyl]-N'-benzyl-urea having a melting point of l6ll63C (from methanol) EXAMPLE N-[4-(,8- Z-methylaminobenzamido -ethyl)- benzenesulfonyl]-N-cyclohexyl-urea 17.7 Grams of N-methyl-isatoic acid anhydride(lmethyl-2H-3,l-benzoxazin-2,4( lH)-dione) were suspended in 50 ml of absolute dimethyl formamide and the solution was heated to 45C. While stirring a solution of 20.2 g of 4-(B-aminoethyl)-benzenesulfonamide in 150 ml of DMF was added dropwise within one hour. Then stirring was continued for 4 hours at 40-50C. The clear solution formed was poured into about 500 ml of water, the 4-(,B 2-methylaminobenzamido ethyl)-benzenesulfonamide was suction-filtered and, after treating with a sodium bicarbonate solution and drying, recrystallized from methanol. Themelting point was l4l-l42C.

6.6 Grams of the sulfonamide thus obtained were dissolved in a mixture of 75 ml of acetone and 10 ml of a 2N sodium hydroxide solution and after cooling with ice, mixed dropwise while stirring with 2.75 g of cyclohexylisocyanate. Having continued stirring for 3 hours at room temperature the deposit formed was dissolved with water, filtered and acidified with 2N acetic acid. The N-[4-(B- 2-methylaminobenzamido ethyl)-benzenesulfonyl]-N-cyclohexyl-urea was suction filtered and recrystallized from methanol/water. It melted at -l77C.

In analogous manner were obtained: N-[4-(B- 2-methylaminobenzamido -ethyl)- benzenesulfonyl]-N'-butyl-urea having a melting point of l55l56C (from methanol/water).

N-[4-(,B- 2-methylaminobenzamido -ethyl)- benzenesulfonyl]-N-(4-methylcyclohexyl)-urea having a melting point of 17 ll73C (from methanol/water) N-[4-(B- 2-methylaminobenzamido -ethyl)- benzenesulfonyl]-N'-cycloheptyl-urea having a melting point of l69170C (from methanol) ln analogous manner was obtained from 4-(B- 5-chloro-2-methylaminobenzamido -ethyl)- benzenesulfonamide (melting point 128l30C, prepared from 5-chloro-N-methyl-isatoic acid anhydride and 4-(B-aminoethyl)-benzenesulfnamide, recrystallized from methanol-dioxane-water the N-[4-(B- 5-chloro-2-methylaminobenzamido ethyl)-benzenesulfonyl]-N-cyclohexyl-urea having a melting point of 196 to 197C (from methanoldioxane-water).

In analogous manner were obtained from the 4-(B- 2-ethylaminobenzamido -ethyl)- benzenesulfonamide (melting point 183C, prepared from N-ethyl-isatoic acid anhydride and 4-(B- aminoethyl)-benzenesulfonamide, recrystallized from methanol/water) the- N-[4-(B- 2-ethylaminobenzamido -ethyl)- benzenesulfonyl]-N'-cyclohexyl-urea having a melting point of 16l-162C (from methanol-dioxane-water) N-[4-(B- 2-ethylaminobenzamido -ethyl)- benzenesulfonyl]-N-butyl-urea having a melting point of 149-l50C (from methanol-dioxane-water).

N-[4-(B- 2-methylaminobenzamido -ethyl)- benzenesulfonyl ]-N 4-methylcyclohe xyl )-urea having a melting point of 188-l90C (from methanoldioxane-water) In analogous manner were obtained from the 4-(,B- 2-ethyl-amino-5-chloro-benzamido -ethyl)- benzenesulfonamide (melting point of l63164C, prepared from N-ethyl-S-chloro-isatoic acid anhydride (melting point of l42-l44C, from ethanol) and 4-(B- aminoethyl)-benzenesulfonamide, recrystallized from methanol-dioxane-water) the N-[4-(B- 2-ethylamino-5-chloro-benzamido ethyl)-benzenesulfonyl]-N-cyclohexyl-urea having a melting point of 186C to 188C (from ethanol) N-[4-(B- 2-ethylamino-5-chloro-benzamido ethyl)-benzenesulfonyl]-N'-butyl-urea having a melting point of l38-140C (from methanol/water) N-[4-(B- 2-ethylamino-5-chloro-benzamido ethyl)-benzenesulfonyl]-N-(4-methylcyclohexyl)-urea having a melting point of 174l76C (from methanoldioxane-water) In analogous manner were obtained from the 4-(B- 2-vutylaminobenzamido -ethyl)- benzenesulfonamide (melting point of l52l53C, prepared from N-butyl-isatoic acid anhydride and 4-(B- 2-aminoethyl)-benzenesulfonamide, recrystallized from methanol/water) the N-[4-(B- 2-butylaminobenzamido -ethyl)- benzenesulfonyl]-N-cyclohexyl-urea having a melting point of l59l60C (from methanol-dioxane-water) N-[4-(B- 2-butylaminobenzamido -ethyl)- benzenesulfonyl]-N'-butyl-urea having a melting point of 156-157C (from methanol/water) N-[4-(/3- 2-butylaminobenzamiclo -ethyl)- benzenesulfonyl ]-N"-( 4-methylcyclohexyl )-urea having a melting point of 169-170C (from methanol/water) ln analogous manner were obtained from the 4-(B- -bromo-2-butylamino-benzamido -ethyl)- benzenesulfonamide (melting point 150151C, prepared from N-butyl-S-bromo-isatoic acid anhydride (melting point of l32-134C from ethanol) and 4-(B- aminoethyl)-benzenesulfonamide, recrystallized from methanol/water) the N-[4-(B- 5-bromo-2-butylamino-benzamido ethyl)-benzenesulfonyl]-N'-cyclohexyl-urea having a melting point of 164166C (from methanol-dioxanewater) I N-[4-(B- 5-bromo-2-butylamino-benzamido ethyl)-benzenesulfonyl]-N'-butyl-urea having a 'melting point of ll53C (from ethanol) N-[4-(B- 5-bromo-2-butylamino-benzamido ethyl )-benzenesulfonyl -N 4-methylcyclohexyl )-urea having a melting point of 169170C (from ethanol) In analogous manner was obtained from the (2- ethylaminobenzamido)-indane-5-sulfonamide (melting point of 211212C, prepared from N-ethyl-isatoic acid anhydride and l-amin0-indane-5-sulfonamide, recrystallized from nitromethane) the N-[2-(2- ethylaminobenzamido)-indane-5-sulfonyl]-N- cyclohexyl-urea having a melting point of 186188C (from ethanol/water) EXAMPLE 6 N- 4-(B- 2-methylaminobenzamido -ethyl benzenesulfonyl]-N'-cyclohexyl-urea 8.85 Grams of N-methyl-isatoic acid anhydride were suspended in 50 ml of absolute DMF and heated to 50C. While stirring, a suspension of 16.3 g of N-[4-(B- aminoethyl)-benzenesulfonyl]-N-cyclohexyl-urea in 50 ml of DMF was added portionwise. Stirring was continued for 4 hours and the mixture was allowed to stand over night. When diluting with 1 liter of water a precipitate was obtained which was suction-filtered and treated with a sodium bicarbonate solution. The remaining product was reprecipitated from diluted ammonia solution with acetic acid. After recrystallization from methanol/water the N-[4-( B- 2- methylaminobenzamido -ethyl)-benzenesulfonyl]-N eyclohexyl-urea melted at 174-176C.

EXAMPLE 7 N-[4-(B- 2-dimethylamino-benzamido -ethyl)- benzenesulfonyl]-N-cyclohexyl-urea 4.9 Grams of N-[4-(B- 2-dimethylaminobenzamido -ethyl)-benzenesulfonyl]-N- cyclohexylthio-urea (melting point of 147-148C, prepared by reaction of 4-(B- 2- dimethylaminobenzamido -ethyl)- benzenesulfonamide with cyclohexyl isothio-cyanate) were dissolved in 250 ml of methanol, mixed with 2.1 g of yellow mercury oxide and spatula point of potassium carbonate and refluxed for 4 hours while stirring. The mercury sulfide was filtered off and the solution was evaporated under reduced pressure. The N-[4-(B- 2-dimethylaminobenzamido -ethyl benzenesulfonyl]-N-cyclohexyl-isourea methyl ether remained as an oily liquid which could not be crystallized and, therefore, was further treated as a crude product;

The oily crude product was dissolved in a small amount of dioxane and heated with 25 ml of 2N- sodium hydroxide solution on the steam bath. After cooling the mixture was acidified with 2N acetic acid and suction-filtered. After recrystallizing from methanol-dioxane-water the N- 4-( ,8- 2- dimethylaminobenzamido -ethyl )-benzenesulf0nyl N'-cyclohexyl-urea melted at 2l22l3C.

EXAMPLE 8 N-[4-(,8- 2-dimethylaminobenzamido -ethyl)- benzenesulfonyl ]-N'-bicyclo(2,2,l )-hept-2-yl-methylurea 7.3 Grams of 4-(B- 2-dimethylamino-benzamido ethyl)-benzene-sulfonamide were dissolved in 20 ml of 2N-sodium hydroxide solution and ml of acetone, cooled to 0C and mixed dropwise with 2.17 g of chloroformic acid methyl ester. The mixture was heated to room temperature and stirring was continued for 2 hours. Subsequently the solvent was evaporated under reduced pressure, the residue was taken up in a diluted ammonia solution, filtered from the undissolved material and acidified with diluted acetic acid. The 4-(B- 2- dimethylaminobenzamido -ethyl )-benzenesulfonylcarbamic acid methyl ester precipitated was suctionfiltered and recrystallized from water and a small amount of methanol; it melted at C to 147C.

4.0 Grams of 4-(B- 2-dimethylaminobanzamido ethyl)-benzenesulfonyl-carbamie acid methyl ester were refluxed in 70 ml of dioxane with 1.3 g of bicyclo- (2,2,1 )-hept-2-yl-methylamine for two hours while stirring. After cooling the mixture was diluted with water and the product was crystallized. After suction-filtering and recrystallizing from methanol the N-[4-(B- 2- dimethylaminobenzamido -ethyl )-benzenesulfonyl N-bicyclo(2,2,1)-hept-2-yl-methyl-urea melted at l56-158C.

In analogous manner were obtained:

The N-[4-(B- 2-dimethylaminobenzamido -ethyl)- benzenesulfonyl]-N'-4-chlorocyclohexyl-urea having a melting point of l58160C (from methanol/water) and the N-[4-(B- Z-dimethylaminobenzamido -ethyl)- benzenesulfonyl ]-N -A -cyclohexeneylmethyl-urea having a melting point of 161C (from methanol).

What is claimed is: l. A sulfonyl-urea of the formula in which X represents hydrogen, chlorine, bromine, methoxy or methyl, Y represents -CH(CH )CH CH -CH(CH or Cl-l CH Z represents hydrogen or together with Y and the phenylene radical the radical 3. A compound as claimed in claim 1, wherein R represents phenyl, R and Z represent hydrogen, R is cyclohexyl, X is chlorine in 5-position to the carbomamide group and Y is the group CH CH 4. A compound as claimed in claim 1, wherein R, or R represent methyl, R, or R hydrogen, R is 4- methylcyclohexyl, X and Z represent hydrogen and Y the group CH CH 5. A compound as claimed in claim 1, wherein R, or R represent ethyl, R or R hydrogen, R is 4- methylcyclohexyl, X is chlorine in 5-position to the carbonamide group, Y is the CH --CH group and 2 represents hydrogen.

6. A compound as claimed in claim 1, wherein R and R represent methyl, R is cycloheptyl, X and Z represent hydrogen and Y the group -CH CH 

2. A compound as claimed in claim 1, wherein R1 and R2 represent methyl, R3 represents 4-methylcyclohexyl, X and Z represent hydrogen and Y the group -CH2-CH2.
 3. A compound as claimed in claim 1, wherein R1 represents phenyl, R2 and Z represent hydrogen, R3 is cyclohexyl, X is chlorine in 5-position to the carbomamide group and Y is the group -CH2-CH2.
 4. A compound as claimed in claim 1, wherein R1 or R2 represent methyl, R1 or R2 hydrogen, R3 is 4-methylcyclohexyl, X and Z represent hydrogen and Y the group -CH2-CH2.
 5. A compound as claimed in claim 1, wherein R1 or R2 represent ethyl, R1 or R2 hydrogen, R3 is 4-methylcyclohexyl, X is chlorine in 5-position to the carbonamide group, Y is the -CH2-CH2- group and Z represents hydrogen.
 6. A compound as claimed in claim 1, wherein R1 and R2 represent methyl, R3 is cycloheptyl, X and Z represent hydrogen and Y the group -CH2-CH2. 